Immune Escape Associated with RBD Omicron Mutations and SARS-CoV-2 Evolution Dynamics

Abstract

The evolution and the emergence of new mutations of viruses affect their transmissibility and/or pathogenicity features, depending on different evolutionary scenarios of virus adaptation to the host. A typical trade-off scenario of SARS-CoV-2 evolution has been proposed, which leads to the appearance of an Omicron strain with lowered lethality, yet enhanced transmissibility. This direction of evolution might be partly explained by virus adaptation to therapeutic agents and enhanced escape from vaccine-induced and natural immunity formed by other SARS-CoV-2 strains. Omicron's high mutation rate in the Spike protein, as well as its previously described high genome mutation rate (Kandeel et al., 2021), revealed a gap between it and other SARS-CoV-2 strains, indicating the absence of a transitional evolutionary form to the Omicron strain. Therefore, Omicron has emerged as a new serotype divergent from the evolutionary lineage of other SARS-CoV-2 strains. Omicron is a rapidly evolving variant of high concern, whose new subvariants continue to manifest. Its further understanding and the further monitoring of key mutations that provide virus immune escape and/or high affinity towards the receptor could be useful for vaccine and therapeutic development in order to control the evolutionary direction of the COVID-19 pandemic.

Keywords: COVID-19; Omicron; RBD mutations; SARS-CoV-2; bioinformatics; immune escape; vaccine development.

Figure 1

Phylogenetic relationships of existing SARS-CoV-2 clades. Clades 19A and 19B are ancestor lineages that emerged in Wuhan. Clade 20A emerged from 19A and was dominant during the European outbreak in March 2020. Clades 20B and 20C are large genetically distinct subclades from 20A that emerged in early 2020. Clades from 20D to 20J emerged over the summer of 2020 and include three Variants of Concern (VoC) [9]: Alpha (lineage B.1.1.7), Beta (lineage B.1.351), Gamma (lineage P.1). Clades from 21A to 21J include the VoC Delta and several Variants of Interest (VoI)—Lambda (lineage C.37), Mu (lineage B.1.621), Epsilon (lineages B.1.429), and some others. Clades 21K (BA.1) and 21L (BA.2) Omicron sublineages emerged from the South Africa strain 21M (lineage B.1.1.529); clades 22A, 22B, and 22C are the currently circulating sublineages of 21L Omicron. Generated by Nextstrain [10,11].

Figure 2

SARS-CoV-2 clade distribution dynamics. Colors are allocated according to Nexstrain Clades: 20B—grey; 20H—purple; 20I—dark blue; 20J—blue; 21A—light blue; 21I—lilac blue; 21J—blue-green; 21L—orange; 21K—orange red. Generated by NextStrain [10,11].

Figure 3

Time dependence of the accumulation rate of mutations in the entire SARS-CoV-2 genome constructed by NextStrain.org, according to GISAID data. Branches in phylogenetic trees were set according to NextClade classification [16]. Generated by NextStrain [10,11].

Figure 4

Dependence of mutation number in the S1 part of the Spike protein from sampling date (top) and divergence (total number of mutations, bottom) in genomes of different SARS-CoV-2 strains; the color code corresponds with different Nexstrain Clades. The analyzed data set was obtained by applying the parameters: “ncov gisaid global” [17]. Generated by NextStrain [10,11].

Figure 5

Time series of important mutations in the RBD of Spike. Generated by NextStrain [10,11]. Amino acid replacements in the RBD sequence at key positions (339/346/371/373/375/417/440/446/452/477/478/484/493/496/498/501/505/547/570) and their frequency in SARS-CoV-2 sublineages: 21A (Delta), 21K (Omicron BA.1), 21K (BA.1 + K346), 21L (Omicron BA.2) from February 2021 to February 2022. Letters indicate amino acids in the same order as the positions were listed above. Colors were allocated according to the different sets of amino acid mutations in the RBD: 21A—mustard; 21L—grey; 21K—orange red; 21K (BA.1 + K346)—green.

Figure 6

Fluctuations of a 7-day moving average for daily lethality and daily COVID-19 cases; data obtained from [78].